Unravelling a new mechanism linking actin polymerization and gene transcription

Abstract

In the recent years, the role of actin and actin-binding proteins in gene transcription has received considerable attention. Nuclear monomeric and polymerized actin and several actin binding proteins have been detected in the mammalian cell nucleus, although their roles in transcription are just beginning to emerge. Our group recently reported that the actin-binding protein Filamin A interacts with the transcriptional coactivator MKL1 to link actin polymerization with transcriptional activity of Serum Response Factor. Here we summarize the regulation and function of MKL1, and highlight this novel mechanism of MKL1 regulation through binding to Filamin A and its implications for cell migration.

Keywords: Filamin A; MAL; MKL1; MRTFA; SRF; actin.

Figure 1.

(A) Model for MKL1 regulation through binding to FLNA in stimulated fibroblasts: LPA stimulation promotes MKL1 nuclear localization due to RhoA-induced stress fiber formation in fibroblasts. FLNA facilitates nuclear actin polymerization and mediates an association between F-actin, FLNA and MKL1 that is required for SRF target gene expression. SRF target genes include cytoskeletal genes and actin itself to ensure sufficient supply of actin to meet the needs for cell motility. (B) Model for MKL1 regulation through binding to G-actin in unstimulated fibroblasts: In serum-starved fibroblasts, binding of monomeric G-actin represses SRF activation and promotes nuclear export of MKL1. (C) FLNA recruitment to the actin promoter. ChIP was performed using FLNA-expressing A7 and FLNA-deficient M2 melanoma cells and a specific antibody against FLNA. Actin and GAPDH (control) promoters were quantified by qRT-PCR from 3 independent chromatin preparations. Values are mean ± SD (n = 3), *p < 0.05.